The present invention relates to bis-benzo or benzopyrido piperidene, piperidylidene and piperazine compounds and to pharmaceutical compositions and methods of using such compounds.
U.S. Pat. Nos. 3,326,924, 3,717,647 and 4,282,233, European published Application No. 0042544 and Villani et al., Journal of Medicinal Chemistry, Vol. 15, No. 7, pp 750-754 (1972) and Arzn. Forsh 36 1311-1314 (1986) describe certain 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines as antihistamines. U.S. Pat. No. 4,355,036 describes certain N-substituted piperidylidene compounds.
International Publication Number WO 89/10369 discloses compounds of the formula: ##STR3## wherein: one of a, b, c and d represents nitrogen or --NR.sup.11 --, wherein R.sup.11 is O.sup.-, --CH.sub.3 or --(CH.sup.2).sub.p CO.sub.2 H wherein p is 1 to 3, and the remaining a, b, c and d groups are CH which may be substituted with R.sup.1 or R.sup.2 ;
R.sup.1 or R.sup.2 may be the same or different and each independently represents halo, --CF.sub.3, --OR.sup.10, --C(O)R.sup.10, --S(O).sub.e R.sup.12 wherein e is 0, 1, or 2, --N(R.sup.10).sub.2, --NO.sub.2, --SH, --CN, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.12, --NR.sup.10 C(O)R.sup.10, alkyl, alkenyl or alkynyl, which alkyl or alkenyl groups may be substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10, or R.sup.1 and R.sup.2 may together form a benzene ring fused to the pyridine ring; PA1 R.sup.10 represents H, alkyl or aryl; PA1 R.sup.12 represents alkyl or aryl; PA1 R.sup.3 and R.sup.4 may be the same or different and each independently represents H or any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 may be taken together to represent a saturated or unsaturated C.sub.5 to C.sub.7 ring fused to the benzene ring; PA1 R.sup.5, R.sup.6, R.sup.7, and R.sup.8 each independently represents H, --CF.sub.3, --CO.sub.2 R.sup.10, --C(O)R.sup.10, alkyl or aryl, which alkyl or aryl may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --C(O)R.sup.10, --OC(O)R.sup.12, --CO.sub.2 R.sup.10 and --OPO.sub.3 (R.sup.10).sub.2, or one of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 may be taken in combination with R as defined below to represent --(CH.sub.2).sub.r wherein r is 1 to 4, said combination being optionally substituted with lower alkyl, lower alkoxy, --CF.sub.3 or aryl, or R.sup.5 may be combined with R.sup.6 to represent .dbd.O or .dbd.S, and/or R.sup.7 may be combined with R.sup.8 to represent .dbd.O or .dbd.S; PA1 T represents carbon or nitrogen, with the dotted line attached to T representing an optional double bond when T is carbon; PA1 m and n are integers 0, 1, 2, or 3, such that the sum of m plus n equals 0 to 3; PA1 when m plus n equals 1, X represents --O--, --S(O).sub.e -- wherein e is 0, 1 or 2, --NR.sup.10 --, --C(O)NR.sub.10 --, --NR.sup.10 C(O)--, --C(S)NR.sup.10 --, --NR.sup.10 C(S)--, --C(O).sub.2 -- or --O.sub.2 C--, wherein R.sup.10 is as defined above; PA1 when m plus n equals 2, X represents --O--, --S(O).sub.e wherein e is 0, 1 or 2, or --NR.sup.10 --; PA1 when m plus n represents 0, X can be any substituent for m plus n equalling 1 and X can also be a direct bond, cyclopropylene or propenylene; PA1 when m plus n equals 3 then X equals a direct bond; PA1 each R.sup.a may be the same or different, and each independently represents H, lower alkyl or phenyl; PA1 Z represents .dbd.O, .dbd.S or .dbd.NR.sup.13 with R.sup.13 equal to R.sup.10 or --CN, wherein R.sup.10 is as defined above, such that PA1 R.sup.1 and R.sup.2 may be the same or different and each independently represents halo, --CF.sub.3, --OR.sup.10, --COR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --OC(O)R.sup.10, --CO.sub.2 R.sup.10, --OCO.sub.2 R.sup.11, alkynyl, alkenyl or alkyl, which alkyl or alkenyl group may be substituted with halo, --OR.sup.10 or --CO.sub.2 R.sup.10 ; PA1 R.sup.3 and R.sup.4 may be the same or different and each independently represents H, any of the substituents of R.sup.1 and R.sup.2, or R.sup.3 and R.sup.4 together may represent a saturated or unsaturated fused C.sub.5 -C.sub.7 ring; PA1 R.sup.5, R.sup.6, R.sup.7 and R.sup.8 each independently represent H, --CF.sub.3, alkyl or aryl, which alkyl or aryl may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2, --NO.sub.2, --COR.sup.10, --OCOR.sup.10, --OCO.sub.2 R.sup.11, --CO.sub.2 R.sup.10, --OPO.sub.3 R.sup.10 or one of R.sup.5, R.sup.6, R.sup.7 and R.sup.8 may be taken in combination with R as defined below to represent --(CH.sub.2).sub.r -- where r is 1 to 4 which may be substituted with lower alkyl, lower alkoxy, --CF.sub.3 or aryl; PA1 R.sup.10 represents H, alkyl or aryl; PA1 R.sup.11 represents alkyl or aryl; PA1 X represents N or C, which C may contain an optional double bond to carbon atom 11; PA1 the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent H, --R.sup.10, --OR.sup.11 or --OC(O)R.sup.10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.10).sub.2, alkyl and H, (alkyl).sub.2, --H and --OC(O)R.sup.10, H and --OR.sup.10, .dbd.O, aryl and H, .dbd.NOR.sup.10 or --O--(CH.sub.2).sub.p --O-- where p is 2, 3 or 4 and R.sup.10 is as previously defined; PA1 Z represents O, S or H.sub.2 such that PA1 (a) when Z is O, R may be taken in combination with R.sup.5, R.sup.6 R.sup.7 or R.sup.8 as defined above, or R represents H, aryl, alkyl, --SR.sup.11, --N(R.sup.10).sub.2, cycloalkyl, alkenyl, alkynyl or --D wherein --D represents heterocycloalkyl, ##STR8## wherein R.sup.3 and R.sup.4 are as previously defined and W is O, S or NR.sup.10 wherein R.sup.10 is as defined above, PA1 said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substituted with from 1-3 groups selected from halo, --CON(R.sup.10).sub.2, aryl, --CO.sub.2 R.sup.10, --OR.sup.12, --SR.sup.12, --N(R.sup.10).sub.2, --N(R.sup.10)CO.sub.2 R.sup.10, --COR.sup.12, --NO.sub.2 or --D, wherein --D and R.sup.10 are as defined above and R.sup.12 represents R.sup.10, --(CH.sub.2).sub.m OR.sup.10 or --(CH.sub.2).sub.q CO.sub.2 R.sup.10 wherein R.sup.10 is as previously defined, m is 1 to 4 and q is 0 to 4, PA1 said alkenyl and alkynyl R groups not containing --OH, --SH or --N(R.sup.10).sub.2 on a carbon containing a double or triple bond respectively; PA1 (b) when Z represents S, R represents in addition to those R groups above, aryloxy or alkoxy; and PA1 (c) when Z represents H.sub.2, R represents --COOR.sup.10, --E--COOR.sup.10 or --E--OR.sup.12 where E is alkanediyl which may be substituted with --OR.sup.10, --SR.sup.10, --N(R.sup.10).sub.2 or --D where D, R.sup.10 and R.sup.12 are as previously defined. These compounds are disclosed as being useful in the treatment of allergy and inflammation. PA1 (1) Canadian Application 780,443, published in the name of Sandoz Patents Ltd.; PA1 (2) Eire 17764, published Apr. 5, 1964 in the name of Sandoz Patents Ltd.; PA1 (3) European Patent Application 81816337.6, Sandoz A. G., published Mar. 10, 1982; PA1 (4) Belgian Application 638,971, Sandoz S. A., published Apr. 21, 1964; PA1 (5) Belgian Application 644,121, Sandoz S. A., published Aug. 20, 1964; PA1 (6) U.S. Pat. No. 4,609,664, issued to Hasspacher on Sep. 2, 1986; PA1 (7) U.S. Pat. No. 3,966,944, issued to Carter on Jun. 29, 1976; PA1 (8) U.S. Pat. No. 3,803,153, issued to Villani on Apr. 9, 1974; PA1 (9) U.S. Pat. No. 3,803,154, issued to Drukker on Apr. 9, 1974; and PA1 (10) U.S. Pat. No. 3,325,501, issued to Ettinsen et al. on Jun. 13, 1967. PA1 X represents an aralkyl- or aryl-containing group having from 6 to 30 carbon atoms or an alkyl group having from 4 to 30 carbon atoms or a cycloalkyl-containing group, which may optionally have substituent(s) and which may be substituted by hetero atom(s) or hetero atom-containing organic group(s) said alkyl group optionally containing unsaturated bond(s); PA1 Y represents a heteroatom or an optionally substituted alkylene chain, the alkylene chain optionally containing hetero atom(s) or unsaturated bond(s); and PA1 A represents an optionally substituted condensed aromatic or heterocyclic ring. PA1 (1) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-Picolyl)piperidine; PA1 (2) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(3-Picolyl)piperidine; and PA1 (3) 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(4-Picolyl)piperidine PA1 R.sup.1, R.sup.2, R.sup.3, and R.sup.4 may be the same or different and each independently represents H, halo, --CF.sub.3,--OR.sup.11, --C(.dbd.O)R.sup.11 , --SR.sup.11, --S(O).sub.e R.sup.13 wherein e is 1 or 2, --N(R.sup.11).sub.2, --NO.sub.2, --OC(.dbd.O)R.sup.11, --CO.sub.2 R.sup.11, CN, --OCO.sub.2 R.sup.13, --NR.sup.11 C(.dbd.O)R.sup.11, alkyl, aryl, alkenyl or alkynyl, which alkyl group may be substituted with --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2 or --CO.sub.2 R.sup.11 and which alkenyl group may be substituted with halo, --OR.sup.13 or --CO.sub.2 R.sup.11 ; PA1 in addition, R.sup.1 and R.sup.2 may together form a benzene ring fused to the ring t and/or R.sup.3 and R.sup.4 may together form a benzene ring fused to the rings; PA1 R.sup.5 and R.sup.6 each independently represents H or alkyl, which alkyl may be substituted with --OR.sup.11, --SR.sup.11 or --N(R.sup.11).sub.2 ; PA1 in addition, R.sup.5 may be combined with R.sup.6 to represent .dbd.O or .dbd.S; PA1 R.sup.7, R.sup.8 and R.sup.9 each independently represents H, halo, --CF.sub.3, --OR.sup.11, --C(O)R.sup.11, --SR.sup.11, --S(O).sub.e R.sup.13 wherein e is 1 or 2, --N(R.sup.11).sub.2, --NO.sub.2, --CO.sub.2 R.sup.11, CN, --OCO.sub.2 R.sup.13, --OCOR.sup.11, alkyl, aryl, alkenyl or alkynyl, which alkyl group may be substituted with --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2, or --CO.sub.2 R.sup.11 and which alkenyl group may be substituted with halo, --OR.sup.13 or --CO.sub.2 R.sup.11 ; PA1 m and n are integers 0, 1 or 3, such that the sum of m plus n equals 0, 1 or 3; PA1 when m plus n equals 0, Y represents --O--, --S(O).sub.e -- (wherein e is 0, 1 or 2), --NR.sup.11 -- or a direct bond; PA1 when m plus n equals 1, Y represents --O--, --S(O).sub.e -- (wherein e is 0, 1 or 2), or --NR.sup.11 --; PA1 when m plus n equals 3, Y represents a direct bond; PA1 R.sup.10 represents H or alkyl; PA1 each R.sup.11 independently represents H, alkyl or aryl; PA1 each R.sup.13 independently represents alkyl or aryl; PA1 each R.sup.14 independently represents H or alkyl; PA1 each R.sup.a independently represents H or lower alkyl; PA1 j represents 1, 2 or 3; PA1 T represents CH, C or N, with the dotted line attached to T representing a double bond when T is C and being absent when T is CH or N; PA1 when Z represents ##STR14## the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B each independently represent --R.sup.11, --OR.sup.13, halo or --OC(O)R.sup.11, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H.sub.2, --(OR.sup.13).sub.2, (alkyl and H), (alkyl).sub.2, (--H and --OC(O)R.sup.11), (H and --OR.sup.11), .dbd.O or .dbd.NOR.sup.14 ; and PA1 with the proviso that when Z represents ##STR15## and X represents CH, and T represents C such that the dotted line attached to T represents a double bond, then L represents N.sup.+ O.sup.-. Preferably, for the compounds of Formula I: R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from the group consisting of H, alkyl, halo, --N(R.sup.11).sub.2, and --OR.sup.11 ; R.sup.5 and R.sup.6 are each independently selected from the group consisting of H and lower alkyl; R.sup.7 and R.sup.8 are each H; R.sup.9 is selected from the group consisting of H, halo, --CF.sub.3, --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2, and lower alkyl, with R.sup.9 most preferably being H; T is selected from the group consisting of N and C; L is the N-oxide (i.e., N.sup.+ O.sup.-), and most preferably L is in the para position relative to the bond connecting the pyridine ring (ring w) to the rest of the compound; j is 1; R.sup.10 is H; and R.sup.11 is selected from the group consisting of H or lower alkyl. PA1 X represents CH, N or N.sup.+ O.sup.- ; PA1 R.sup.7 and R.sup.8 each independently represent H, halo, --CF.sub.3, --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2, alkyl, aryl, alkenyl or alkynyl; PA1 with the proviso that when X represents CH, and T represents C such that the dotted line attached to T represents a double bond, then L represents N.sup.+ O.sup.- ; and PA1 all other substituents for Formula Ib are as defined above for Formula I. PA1 R.sup.7 and R.sup.8 each independently represent H, halo, --CF.sub.3, --OR.sup.11, --SR.sup.11, --N(R.sup.11).sub.2, alkyl, aryl, alkenyl or alkynyl; PA1 Z represents --C(R.sup.a).sub.2 --Y--, --Y--C(R.sup.a).sub.2 --, --Y--, --CH.sub.2 CH.sub.2 CH.sub.2 -- or a direct bond where Y represents --O--, --S--, --NR.sup.10 ; and PA1 all of the other substituents in Formula Ik are as defined above for Formula I.
(a) when Z is O, R may be taken in combination with R.sup.5, R.sup.6, R.sup.7 or R.sup.8 as defined above, or R represents H, alkyl, aryl, --SR.sup.12, --N(R.sup.10).sub.2, cycloalkyl, alkenyl, alkynyl or --D wherein --D represents heterocycloalkyl, ##STR4## wherein R.sup.3 and R.sup.4 are as previously defined, and W is O, S or NR.sup.10, and wherein Y is N or NR.sup.11, said cycloalkyl, alkyl, alkenyl and alkynyl being optionally substituted with from 1-3 groups selected from halo, --CON(R.sup.10).sub.2, aryl, --CO.sub.2 R.sup.10, --OR.sup.14, --SR.sup.14, --N(R.sup.10).sub.2, --N(R.sup.10)CO.sub.2 R.sup.10, --COR.sup.14, --NO.sub.2 or --D, wherein --D and R.sup.10 are as defined above and R.sup.14 represents R.sup.10, --(CH.sub.2).sub.r OR.sup.10 or --(CH.sub.2).sub.q CO.sub.2 R.sup.10 wherein r is 1 to 4, q is 0 to 4; said alkenyl and alkynyl R groups not containing --OH, --SH, or --N(R.sup.10).sub.2 on a carbon in a double or triple bond respectively; and PA2 (b) when Z represents .dbd.S, R represents in addition to those R groups above, aryloxy or alkoxy; and PA2 (c) where Z represents .dbd.NR.sup.13, R represents H, alkyl, aryl, N(R.sup.10).sub.2, cycloalkyl, alkenyl or alkynyl.
WO 89/10369 generically discloses compounds which can have the structure: ##STR5## wherein Z can be O and R can be: ##STR6## wherein Y can be NR.sup.11 and R.sup.11 can be --O.sup.- ; however, no specific compounds are disclosed with this structure.
U.S. Pat. No. 4,826,853 issued to Piwinski et al. on May 2, 1989 is the priority document for WO 88/03138 which published on May 5, 1988. WO 88/03138 discloses compounds of the formula ##STR7## or a pharmaceutically acceptable salt or solvate thereof, wherein: one of a, b, c and d represents N or NR.sup.9 where R.sup.9 is O --CH.sub.3 or --(CH.sub.2).sub.n CO.sub.2 H where n is 1 to 3, and the remaining a, b, c and d groups are CH, which remaining a, b, c and d groups optionally may be substituted with R.sup.1 or R.sup.2 ;
During the course of our research on the compounds disclosed in WO 88/03138, we generally found that the compounds having a carbonyl group (Z.dbd.O) attached to the piperidyl, piperidylidenyl or piperazinyl nitrogen atom were much stronger antagonists of platelet activating factor (PAF) than the compounds having a CH.sub.2 group (Z.dbd.H.sub.2) attached thereto.
WO 90/13548 published on Nov. 15, 1990 on PCT/US90/02251 which was filed on Apr. 30, 1990 and claims priority to U.S. application Ser. No. 345,604 filed May 1, 1989 discloses compounds similar in structure to the compounds disclosed in WO 88/03138 with the difference being that the R group represents an N-oxide heterocyclic group of the formula (i), (ii), (iii), or (iv): ##STR9## wherein R.sup.9, R.sup.10, and R.sup.11 can be, amongst other groups, H.
Copending U.S. application Ser. No. 625,261 filed on Dec. 10, 1990 is related to WO 90/13548.
The following references have disclosed oxygen or sulfur in the bridgehead of the three ring portion of the molecule:
None of references (1) to (10) above disclose substitution on the piperidylidene nitrogen similar to that described below for the compounds of this invention.
European Patent Application, Publication No. 0 371 805, published Jun. 6, 1990, priority based on Japanese 303461/88 (30 Nov. 88) and JP64059/89 (16 Mar. 89) discloses compounds useful as hypotensives having the formula: ##STR10## wherein: any of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 may be the same or different from each other and each independently represents a hydrogen atom or other substituent;
European Patent Publication No. 0 371 805 also discloses that if present, the aromatic ring of X or A is benzene, pyridine, pyridazine, or pyrazine, amongst others (see page 3 at about lines 35-40).
Amongst the specific compounds disclosed in European Patent Publication No. 0 371 805, there is included:
--(see page 34 at about lines 36-38). It is believed the structures of these compounds are: ##STR11##